Nitrosylation The Prototypic Redox-Based Signaling Mechanism

posttranslational modifications of proteins operate by of Medicine and Biochemistry shifting a dynamic equilibrium between inactive and ac-in particular has served as a model of how protein modi-2 Centro de Investigaciones Biologicas fication triggers conformational changes that regulate Instituto " Reina Sofia " de Investigaciones Nefrologicas signal transduction. These fundamental concepts of al-Consejo Superior de Investigaciones Cientificas losteric regulation in fact originate in studies of the post-Velazquez 144 translational modification of hemoglobin by small di-28006 Madrid atomic ligands. Thus, whereas phosphorylation clearly Spain lies at the heart of many signal transduction pathways, has been expanded re-translational modification of proteins, are conserved cently by the discovery of an enzymatic function for throughout evolution and influence most aspects of cel-hemoglobin, operating within the confines of a mem-lular physiology—one is phosphorylation and the other brane-localized signaling module by binding to its target is redox based. Both exemplify dynamic regulation of protein and introducing NO groups (much as a kinase protein function by reversible modification, and they introduces phosphates) (Pawloski et al., 2001). In this govern many of the same signal transduction pathways case, a redox-based signal that is initiated through an through overlapping sets of cellular targets. They are O 2-induced allosteric transition in hemoglobin is propa-also prone to malfunction in human disease. However, gated by S-nitrosylation of an anion exchanger to sub-while many basic principles of signal transduction have serve intercellular communication. emerged from studies of phosphorylation, the redox-Two key themes have emerged from these studies of based mechanism has remained far more enigmatic. A hemoglobin: (1) the importance of allostery in posttrans-major difficulty has been to comprehend how specificity lational modification of proteins by NO, and (2) the role of action is achieved. Recent advances in understanding of O 2 /redox as an allosteric effector. The ryanodine re-how nitric oxide (NO) regulates protein function are now ceptor/calcium release channel (RyR), which is con-ogy to hemoglobin, in terms of an equilibrium between 6/675/DC1). Second, the majority of these proteins are two alternative structures that is governed by O 2 tension. regulated by S-nitrosylation of a single critical cysteine In this model, a redox-driven conformational change in residue within an acid-base or hydrophobic structural the channel provides a hydrophobic compartment that motif, which may also be subject to oxygen-or glutathi-concentrates NO and O 2 , thus generating nitrosylating one-dependent modification. Thus, S-nitrosylation equivalents. The observation that S-nitrosylation acti-emerges as a prototypic redox-based signal. …